Abstract
BackgroundIn sprouting angiogenesis, VEGFR2 level is regulated via a fine-tuned process involving various signaling pathways. Other than VEGF/VEGFR2 signaling pathway, Wnt/ β-catenin signaling is also important in vascular development. However, the crosstalk between these two signaling pathways is still unknown to date. In this study, we aimed to investigate the role of DIX domain containing 1 (DIXDC1) in vasculature, facilitating the crosstalk between VEGF/VEGFR2 and Wnt/ β-catenin signaling pathways.ResultsIn mice, DIXDC1 deficiency delayed angiogenesis at the embryonic stage and suppressed neovascularization at the neonatal stage. DIXDC1 knockdown inhibited VEGF-induced angiogenesis in endothelial cells in vitro by downregulating VEGFR2 expression. DIXDC1 bound Dishevelled Segment Polarity Protein 2 (Dvl2) and polymerized Dvl2 stabilizing VEGFR2 protein via its direct interaction. The complex formation and stability of VEGFR2 was potentiated by Wnt signaling. Moreover, hypoxia elevated DIXDC1 expression and likely modulated both canonical Wnt/β-catenin signaling and VEGFR2 stability in vasculatures. Pathological angiogenesis in DIXDC1 knockout mice was decreased significantly in oxygen-induced retinopathy (OIR) and in wound healing models. These results suggest that DIXDC1 is an important factor in developmental and pathological angiogenesis.ConclusionWe have identified DIXDC1 as an important factor in early vascular development. These results suggest that DIXDC1 represents a novel regulator of sprouting angiogenesis that links Wnt signaling and VEGFR2 stability and may have a potential role in pathological neovascularization.
Highlights
In sprouting angiogenesis, Vascular endothelial growth factor receptor2 (VEGFR2) level is regulated via a fine-tuned process involving various signal‐ ing pathways
E, F), suggesting delayed embryonic development in the DIX domain containing 1 (DIXDC1)-KO mice. These results suggest that DIXDC1 is an important factor in developmental angiogenesis, both at the embryonic and early postnatal stages
DIXDC1 binds Dishevelled Segment Polarity Protein 2 (Dvl2), and the polymerized Dvl2 in turn stabilizes VEGFR2 via direct interaction. These findings strongly suggest that DIXDC1 is an important regulator of angiogenesis that modulates Wnt signaling, which increases the stability of VEGFR2 in sprouting tip cells
Summary
VEGFR2 level is regulated via a fine-tuned process involving various signal‐ ing pathways. We aimed to investigate the role of DIX domain containing 1 (DIXDC1) in vasculature, facilitating the crosstalk between VEGF/VEGFR2 and Wnt/ β-catenin signaling pathways. Angiogenesis, the formation of new blood vessels from an existing vasculature, plays an essential role in embryogenesis and is associated with the pathogenesis of various human disorders [1,2,3]. The role of VEGF-A/VEGFR2 signaling in tip and stalk cell determination of developing vascular trees is well recognized. Spatial and timely crosstalk between VEGFR2 and Notch pathways is essential for vascular pattern formation [13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
